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Exposed to ubiquitously perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with non-alcoholic fatty liver disease (NAFLD), yet the underlying molecular mechanism remains elusive. The extrapolation of empirical studies correlating per- and polyfluoroalkyl substance (PFAS) exposure with NAFLD occurrence to real-life exposure was hindered by the limited availability of mechanistic data at environmentally relevant concentrations. Herein, a novel pathway mediating hepatocyte lipid accumulation by PFOA and PFOS at human-relevant dose (<10 μM) was identified by integrating CRISPR-Cas9 genome screening, concentration-dependent transcriptional assay in HepG2 cell and epidemiological data mining. 1) At genetic level, nudt7 showed the highest enriched potency among 569 NAFLD-related genes, and the transcription of nudt7 was significantly downregulated by PFOA and PFOS exposure (<7 μM). 2) At molecular pathway, upon exposure to ≤10 -4  μM PFOA and PFOS, the downregulation of nudt7 transcriptional expression triggered the reduction of Ace-CoA hydrolase activity. 3) At cellular level, increased lipids were measured in HepG2 cells with PFOA and PFOS (<2 μM). Overall, we identified a novel mechanism mediated by transcriptional downregulation of nudt7 gene in hepatocellular lipid increase treated with PFOA and PFOS, which could potentially explain the NAFLD occurrence associated with exposure to PFASs in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

PFOA is a legacy Per- and Polyfluorinated Substances (PFAS), a group of chemicals widely used in various industrial applications and consumer products. Although there has been a voluntary phase out of PFOA since 2005, it is still widely detected in various water supplies. A growing body of evidence suggests an association between PFOA exposure, particularly during developmental stages, with increased risks of neurodegenerative diseases (NDs). The neurotoxic mechanism of developmental PFOA exposure, however, remains poorly understood. Utilizing human induced-pluripotent stem cell (hiPSC)-derived cortical neurons, we investigated the effect of PFOA exposure prior to differentiation and assessed changes in neuronal characteristics, transcriptome, and neurodegeneration markers mimicking a Developmental Origin of Health and Disease (DoHAD) paradigm. Exposure to PFOA before neuron differentiation resulted in persistent alterations in nuclear morphology, neuronal network, and calcium activity. RNA sequencing analysis further revealed transcriptomic changes aligning with Alzheimer's Disease (AD) after PFOA exposure. These observations were further corroborated by alterations in tau phosphorylation markers, the presence of fibrillar tau, an increase in liquid droplets, and a decrease in RNA translational efficiency characterized using a battery of biochemical assays. Taken together, our results revealed persistent deficits of key neuronal characteristics induced by pre-differentiation PFOA exposure, suggesting impairments in several AD-related pathways that can together contribute to the elevation of AD risk after pre-differentiation PFOA exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Perfluorooctanoic acid (PFOA), a member of per- and polyfluoroalkyl substances (PFASs), has been widely used in manufacturing for decades. Currently, PFOA is strictly regulated, but due to its high stability and persistence, it is detected in both environmental as well as in human matrices. To elucidate mechanisms of PFOA toxicity in humans, we determined the genome-wide transcriptomic changes of peripheral blood mononuclear cells (PBMC) responding to PFOA exposure in a sex-stratified analysis. This work employed samples from 145 female and 143 male participants of the CELSPAC: YA study to characterize PFOA-associated transcripts in a broader context using computational analysis. PFOA-associated gene expression differed significantly between men and women, as only 2 % of mapped genes were expressed in both sexes. Disease-specific enrichment analysis revealed cancer and immune-related disease terms as those most enriched in male and female populations. Patterns of enriched terms within the gene set enrichment analysis indicated three main targets of PFOA toxicity: i) lipid metabolism for women; ii) cell cycle regulation for men; and iii) immune system response for both sexes. In summary, our genome-wide transcriptomics analysis described sex-specific differences in PFOA-associated gene expression and provided evidence about biological pathways underlying PFOA toxicity in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

As alternatives of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimeric acid (HFPO-DA) and trimeric acid (HFPO-TA) have been detected increasingly in environmental media and even humans. They have been shown to exhibit reproductive toxicity to model species, but their effects on human remain unclear due to the knowledge gap in their mode of action. Herein, (anti-)androgenic effects of the two HFPOs and PFOA were investigated and underlying toxicological mechanism was explored by combining zebrafish test, cell assay and molecular docking simulation. Exposure of juvenile zebrafish to the chemicals during sex differentiation promoted feminization, with HFPO-TA acting at an environmental concentration of 1 μg/L. The chemicals inhibited proliferation of human prostate cells and transcriptional activity of human and zebrafish androgen receptors (AR), with HFPO-TA displaying the strongest potency. Molecular docking revealed that the chemicals bind to AR in a conformation similar to a known AR antagonist. Combined in vivo, in vitro and in silico results demonstrated that the chemicals disrupted sex differentiation likely by antagonizing AR-mediated pathways, and provided more evidence that HFPO-TA is not a safe alternative to PFOA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that have attracted considerable attention due to their widespread utilization, resilient characteristics, adverse health implications, and regulatory scrutiny. Despite documented toxicity in living organisms, the precise molecular mechanisms governing the induced adverse effects remain unclear. This study aims to elucidate mechanisms of toxic action by collecting empirical data sets along oxidative stress and metabolic disruption pathways. We investigated the impact of long-chain PFAS (perfluorooctanoic acid (PFOA)) and its short-chain analog (perfluorobutanoic acid (PFBA)) on human neuronal cells (SH-SY5Y). The functionalities of enzymes associated with oxidative stress (catalase and glutathione reductase) and cellular metabolism (lactate dehydrogenase and pyruvate dehydrogenase) were also characterized. Our results reveal that a 24-hour exposure to PFOA and PFBA generated significant levels of reactive oxygen species. Correspondingly, there was a notable decline in catalase and glutathione reductase activities, with PFBA demonstrating a more pronounced effect. High concentrations of PFOA and PFBA reduced metabolic activity. Lactate dehydrogenase activity was only impacted by a high concentration of PFBA, while pyruvate dehydrogenase activity was decreased with PFBA exposure and increased with PFOA exposure. The findings from this study contribute to the knowledge of PFAS and cell interactions and reveal the potential underlying mechanisms of PFAS-induced toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10 -8 M to 4 × 10 -7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Exposure to environmental pollutants is suspected to be one of the potential causes accounting for the increase in thyroid cancer (TC) incidence worldwide. Among the ubiquitous pollutants, per-polyfluoroalkyl substances (PFASs), were demonstrated to exert thyroid disrupting effects. Perfluoroalkyl carboxylates (PFCAs) represent a subgroup of PFAS and include perfluoro carboxylic acids (PFOA and PFHxA) and perfluoropolyether carboxylic acid (C6O4). The potential relationship between exposure to PFCAs and TC was not yet fully elucidated. This in vitro study investigated whether certain PFCAs (C6O4, PFOA, and PFHxA) can influence the composition of TC microenvironment., Methods: Two models of normal thyroid cells in primary cultures: Adherent (A-NHT) and Spheroids (S-NHT) were employed. A-NHT and S-NHT were exposed to C6O4, PFOA or PFHxA (0; 0.01; 0.1, 1; 10; 100; 1000 ng/mL) to assess viability (WST-1 and AV/PI assay), evaluate spherification index (SI) and volume specifically in S-NHT. CXCL8 and CCL2 (mRNA and protein), and EMT-related genes were assessed in both models after exposure to PFCAs., Results: PFHxA reduced the viability of both A-NHT and S-NHT. None of the PFCAs interfered with the volume or spherification process in S-NHT. CXCL8 and CCL2 mRNA and protein levels were differently up-regulated by each PFCAs, being PFOA and PFHxA the stronger inducers. Moreover, among the tested PFCAs, PFHxA induced a more consistent increase in the mRNA levels of EMT-related genes., Conclusions: This is the first evaluation of the effects of exposure to PFCAs on factors potentially involved in establishing the TC microenvironment. PFHxA modulated the TC microenvironment at three levels: cell viability, pro-tumorigenic chemokines, and EMT-genes. The results provide further evidence of the pro-tumorigenic effect of PFOA. On the other hand, a marginal effect was observed for C6O4 on pro-tumorigenic chemokines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research was supported by Solvay Specialty Polymers Italy S.p.A. The commissioning partly funded the consumables and personnel used in this study. The funder had no role in planning or executing the research, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposing marine organisms to contemporary contaminants, such as perfluorooctanoic acid (PFOA) and nano-titanium dioxide (nano-TiO 2 ), can induce multifaceted physiological consequences. Our investigation centered on the responses of the mussel, Mytilus coruscus, to these agents. We discerned pronounced disruptions in gill filament connections, pivotal structures for aquatic respiration, suggesting compromised oxygen uptake capabilities. Concurrently, the respiratory rate exhibited a marked decline, indicating a respiratory distress. Furthermore, the mussels' clearance rate, a metric of their filtration efficacy, diminished, suggesting the potential for bioaccumulation of deleterious substances. Notably, the co-exposure of PFOA and nano-TiO 2 exhibits interactive effects on the physiological performance of the mussels. The mussels' digestive performance waned in the face of heightened PFOA and nano-TiO 2 concentrations, possibly hampering nutrient assimilation and energy accrual. This was mirrored in the noticeable contraction of their energy budget, suggesting long-term growth repercussions. Additionally, the dysregulation of the gut microbiota and the reduction in its diversity further confirm alterations in intestinal homeostasis, subsequently impacting its physiological functions and health. Collectively, these findings underscore the perils posed by escalated PFOA and nano-TiO 2 levels to marine mussels, accentuating the need for a deeper understanding of nanoparticle-pollutant synergies in marine ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Poly- and perfluoroalkyl substances (PFAS) are frequently detected in the environment and are linked to adverse reproductive health outcomes in humans. Although legacy PFAS have been phased out due to their toxicity, alternative PFAS are increasingly used despite the fact that information on their toxic effects on reproductive traits is particularly scarce. Here, we exposed male guppies (Poecilia reticulata) for a short period (21 days) to an environmentally realistic concentration (1 ppb) of PFOA, a legacy PFAS, and its replacement compound, GenX, to assess their impact on reproductive traits and gene expression. Exposure to PFAS did not impair survival but instead caused sublethal effects. Overall, PFAS exposure caused changes in male sexual behaviour and had detrimental effects on sperm motility. Sublethal variations were also seen at the transcriptional level, with the modulation of genes involved in immune regulation, spermatogenesis, and oxidative stress. We also observed bioaccumulation of PFAS, which was higher for PFOA than for GenX. Our results offer a comprehensive comparison of these two PFAS and shed light on the toxicity of a newly emerging alternative to legacy PFAS. It is therefore evident that even at low concentrations and with short exposure, PFAS can have subtle yet significant effects on behaviour, fertility, and immunity. These findings underscore the potential ramifications of pollution under natural conditions and their impact on fish populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lithium Bis(trifluoromethanesulfonyl)imide (LiTFSI ie. HQ-115), a polymer electrolyte used in energy applications, has been detected in the environment, yet its health risks and environmental epigenetic effects remain unknown. This study aims to unravel the potential health risks associated with LiTFSI, investigate the role of DNA methylation-induced toxic mechanisms in its effects, and compare its hepatotoxic impact with the well-studied Perfluorooctanoic Acid (PFOA). Using a murine model, six-week-old male CD1 mice were exposed to 10 and 20 mg/kg/day of each chemical for 14 days as 14-day exposure and 1 and 5 mg/kg/day for 30 days as 30-day exposure. Results indicate that PFOA exposure induced significant hepatotoxicity, characterized by liver enlargement, and elevated serum biomarkers. In contrast, LiTFSI exposure showed lower hepatotoxicity, accompanied by mild liver injuries. Despite higher bioaccumulation of PFOA in serum, LiTFSI exhibited a similar range of liver concentrations compared to PFOA. Reduced Representative Bisulfite Sequencing (RRBS) analysis revealed distinct DNA methylation patterns between 14-day and 30-day exposure for the two compounds. Both LiTFSI and PFOA implicated liver inflammatory pathways and lipid metabolism. Transcriptional results showed that differentially methylated regions in both exposures are enriched with cancer/disease-related motifs. Furthermore, Peroxisome proliferator-activated receptor alpha (PPARα), a regulator of lipid metabolism, was upregulated in both exposures, with downstream genes indicating potential oxidative damages. Overall, LiTFSI exhibits distinct hepatotoxicity profiles, emphasizing the need for comprehensive assessment of emerging PFAS compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Exposure to persistent organic pollutants during the perinatal period is of particular concern because of the potential increased risk of neurological disorders in adulthood. Here we questioned whether exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) could alter myelin formation and regeneration. First, we show that PFOS, and to a lesser extent PFOA, accumulated into the myelin sheath of postnatal day 21 (p21) mice, whose mothers were exposed to either PFOA or PFOS (20 mg/L) via drinking water during late gestation and lactation, suggesting that accumulation of PFOS into the myelin could interfere with myelin formation and function. In fact, PFOS, but not PFOA, disrupted the generation of oligodendrocytes, the myelin-forming cells of the central nervous system, derived from neural stem cells localised in the subventricular zone of p21 exposed animals. Then, cerebellar slices were transiently demyelinated using lysophosphatidylcholine and remyelination was quantified in the presence of either PFOA or PFOS. Only PFOS impaired remyelination, a deleterious effect rescued by adding thyroid hormone (TH). Similarly to our observation in the mouse, we also showed that PFOS altered remyelination in Xenopus laevis using the Tg(Mbp:GFP-ntr) model of conditional demyelination and measuring, then, the number of oligodendrocytes. The functional consequences of PFOS-impaired remyelination were shown by its effects using a battery of behavioural tests. In sum, our data demonstrate that perinatal PFOS exposure disrupts oligodendrogenesis and myelin function through modulation of TH action. PFOS exposure may exacerbate genetic and environmental susceptibilities underlying myelin disorders, the most frequent being multiple sclerosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Perfluoroalkyl acids (PFAAs) within the broader class of per- and polyfluoroalkyl substances (PFAS) are present in human serum as isomer mixtures, but epidemiological studies have yet to address isomer-specific associations with child development and behavior., Objectives: To examine associations between prenatal exposure to 25 PFAAs, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) isomers, and child neurodevelopment among 490 mother-child pairs in a prospective Canadian birth cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. To consider the influence of a classic neurotoxicant, total mercury (THg), based on its likelihood of co-exposure with PFAAs from common dietary sources., Methods: Maternal blood samples were collected in the second trimester and child neurodevelopment was assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). Linear or curvilinear multiple regression models were used to examine associations between exposures and neurodevelopment outcomes., Results: Select PFAAs were associated with lower Cognitive composite scores, including perfluoroheptanoate (PFHpA) (β = -0.88, 95% confidence interval (CI): -1.7, -0.06) and perfluorododecanoate (PFDoA) (β = -2.0, 95% CI: -3.9, -0.01). Non-linear relationships revealed associations of total PFOS (β = -4.4, 95% CI: -8.3, -0.43), and linear-PFOS (β = -4.0, 95% CI: -7.5, -0.57) and 1m-PFOS (β = -1.8, 95% CI: -3.3, -0.24) isomers with lower Language composite scores. Although there was no effect modification, including THg interaction terms in PFAA models revealed negative associations between perfluorononanoate (PFNA) and Motor (β = -3.3, 95% CI: -6.2, -0.33) and Social-Emotional (β = -3.0, 95% CI: -5.6, -0.40) composite scores., Discussion: These findings reinforce previous reports of adverse effects of maternal PFAA exposure during pregnancy on child neurodevelopment. The unique hazards posed from isomers of PFOS justify isomer-specific analysis in future studies. To control for possible confounding, mercury co-exposure may be considered in studies of PFAAs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluorooctanoic acid (PFOA) is a synthetic perfluorinated compound that is extensively used as an integral surfactant in commercial production. Owing to its hydrophilicity and persistence, PFOA can accumulate in living organisms and induce severe disease in animals and humans. It has been reported that PFOA exposure can affect ovarian function and induce reproductive toxicity; however, the effects and potential mechanism of PFOA exposure during gestation on early embryonic development and offspring remain unclear. This study found that PFOA exposure in vitro disrupted spindle assembly and chromosome alignment during the first cleavage of early mouse embryos, which impacted early embryonic cleavage and blastocyst formation. Moreover, PFOA exposure caused mitochondrial dysfunction and oxidative stress by inducing aberrant Ca 2+ levels, liquid drops(LDs), and mitochondrial membrane potential in the 2-cell stage. Furthermore, we found that PFOA exposure resulted in DNA damage, autophagy, and apoptosis in 2-cell stage by inhibiting SOD2 function. Gestational exposure to PFOA significantly increased ovarian apoptosis and disrupted follicle development in F1 offspring. In addition, oocyte maturation competence was decreased in F1 offspring. Finally, single-cell transcriptome analysis revealed that PFOA-induced oocyte deterioration was caused by mitochondrial dysfunction and apoptosis in the F1 offspring. In summary, our results indicated that gestational exposure to PFOA had potential toxic effects on ovarian function and led to a higher incidence of meiotic defects in F1 female offspring., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The quality of irrigation water and drainage water is essential for local ecosystem and human health in agricultural regions. In this study, the transport analysis, source identification, and environmental risk assessment of perfluoroalkyl acids (PFAAs) were conducted in the largest irrigation area in northern China. The concentrations of the total PFAAs (ΣPFAA) ranged from 41.5 to 263 ng/L in surface water, and the short-chain perfluoroalkyl carboxylic acids (PFCAs) and perfluorooctanoic acid (PFOA), were dominant with a total contribution of 94%. Generally, the ΣPFAA levels increased from irrigation waters to drainage and receiving lake waters. PFOA showed the highest increase, with potential emission sources located in the catchment of the sub main drainage ditch D5. More PFOA (36.8 kg/y) was outflowed from Ulansuhai Lake to the Yellow River than that inflowed from the Yellow River to the irrigation district (6.15 kg/y). The results of a risk assessment indicated that avian wildlife living in Ulansuhai Lake were threatened by the PFOA and perfluorobutane sulfonate (PFBS) pollution. The estimated daily intakes (EDIs) of the sum of the PFOA, perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) through aquatic food consumption for people with the different aquatic food preferences accounted for 6-42% (urban) and 4-27% (rural) of the strictest tolerant daily intake (TDI) value. The results of this study highlight the impact of local emissions of PFAS on massive irrigation and drainage systems, and ultimately, the ecosystem and human health., (Copyright © 2021. Published by Elsevier Ltd.)

Due to its potential adverse effects on human health, perfluorooctanoic acid (PFOA), one of the once widely used legacy per- and polyfluoroalkyl substances (PFASs), has been recently replaced by its novel alternatives including hexafluoropropylene-oxide-dimer-acid (GenX) and ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA). These alternative PFASs are detected in water and exposed workers. PFASs can enter organs like thyroids, however, it is yet unknown whether the new alternatives are safer than PFOA. In the current study, we compared the thyroid disrupting effects of PFOA and its alternatives GenX and ADONA in vitro with both rat thyroid cell line FRTL5 and primary normal human thyroid (NHT) cells. Cells were exposed to ascendant doses of PFOA, GenX or ADONA for various incubation time and cell viability was assessed by WST-1 assay and LDH assay. The proliferation rate of survived cells was determined by crystal violet-based cell proliferation assay and MTT assay. The gene expression of thyroid hormone regulation-related genes in thyroid cells after exposure was quantified by RT-PCR and Western blot. Our data showed that both PFOA and GenX reduced thyroid cell viability in both dose and time dependent manner, with GenX being more toxic than PFOA at the same condition. Similarly, the proliferation rate of cells survived exposure to PFOA and GenX was considerably impaired, with GenX showing more profound adverse effect than PFOA. Unlike PFOA and GenX, ADONA showed no apparent adverse effects on the viability and proliferation of both thyroid cell types. Gene expression data revealed that all three PFASs altered gene expression in both thyroid cells and the altered gene expression seemed to be PFAS and cell type dependent. Taken together, our data reveal that the thyroid disrupting effects is increased in the order of GenX > PFOA > ADONA. Our findings will be beneficial for the guidance of the future usage of PFASs and development of better alternatives., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: The growing impact of the COVID-19 pandemic has heightened the urgency of identifying individuals most at risk of infection. Per- and poly-fluoroalkyl substances (PFASs) are manufactured fluorinated chemicals widely used in many industrial and household products. The objective of this case-control study was to assess the association between PFASs exposure and COVID-19 susceptibility and to elucidate the metabolic dysregulation associated with PFASs exposure in COVID-19 patients., Methods: Total 160 subjects (80 COVID-19 patients and 80 symptom-free controls) were recruited from Shanxi and Shandong provinces, two regions heavily polluted by PFASs in China. Twelve common PFASs were quantified in both urine and serum. Urine metabolome profiling was performed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)., Results: In unadjusted models, the risk of COVID-19 infection was positively associated with urinary levels of perfluorooctanesulfonic acid (PFOS) (Odds ratio: 2.29 [95% CI: 1.52-3.22]), perfluorooctanoic acid (PFOA) (2.91, [1.95-4.83], and total PFASs (∑ (12) PFASs) (3.31, [2.05-4.65]). After controlling for age, sex, body mass index (BMI), comorbidities, and urine albumin-to-creatinine ratio (UACR), the associations remained statistically significant (Adjusted odds ratio of 1.94 [95% CI: 1.39-2.96] for PFOS, 2.73 [1.71-4.55] for PFOA, and 2.82 [1.97-3.51] for ∑ (12) PFASs). Urine metabolome-PFASs association analysis revealed that 59% of PFASs-associated urinary endogenous metabolites in COVID-19 patients were identified to be produced or largely regulated by mitochondrial function. In addition, the increase of PFASs exposure was associated with the accumulation of key metabolites in kynurenine metabolism, which are involved in immune responses (Combined β coefficient of 0.60 [95% CI: 0.25-0.95, P = 0.001]). Moreover, alternations in PFASs-associated metabolites in mitochondrial and kynurenine metabolism were also correlated with clinical lab biomarkers for mitochondrial function (serum growth/differentiation factor-15) and immune activity (lymphocyte percentage), respectively., Conclusion: Elevated exposure to PFASs was independently associated with an increased risk of COVID-19 infection. PFASs-associated metabolites were implicated in mitochondrial function and immune activity. Larger studies are needed to confirm our findings and further understand the underlying mechanisms of PFASs exposure in the pathogenesis of SARS-CoV2 infection., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The C8 Science Panel was composed of three epidemiologists charged with studying the possible health effects of PFOA in a highly exposed population in the mid-Ohio Valley. The Panel determined in 2012 there was a 'probable link' (i.e., more probable than not based on the weight of the available scientific evidence) between PFOA and high cholesterol, thyroid disease, kidney and testicular cancer, pregnancy-induced hypertension, and ulcerative colitis., Objective: Here, former C8 Science Panel members and collaborators comment on the PFOA literature regarding thyroid disorders, cancer, immune and auto-immune disorders, liver disease, hypercholesterolemia, reproductive outcomes, neurotoxicity, and kidney disease. We also discuss developments regarding fate and transport, and pharmacokinetic models, and discuss causality assessment in cross-sectional associations among low-exposed populations., Discussion: For cancer, the epidemiologic evidence remains supportive but not definitive for kidney and testicular cancers. There is consistent evidence of a positive association between PFOA and cholesterol, but no evidence of an association with heart disease. There is evidence for an association with ulcerative colitis, but not for other auto-immune diseases. There is good evidence that PFOA is associated with immune response, but uneven evidence for an association with infectious disease. The evidence for an association between PFOA and thyroid and kidney disease is suggestive but uneven. There is evidence of an association with liver enzymes, but not with liver disease. There is little evidence of an association with neurotoxicity. Suggested reductions in birthweight may be due to reverse causality and/or confounding. Fate and transport models and pharmacokinetic models remain central to estimating past exposure for new cohorts, but are difficult to develop without good historical data on emissions of PFOA into the environment., Conclusion: Overall, the epidemiologic evidence remains limited. For a few outcomes there has been some replication of our earlier findings. More longitudinal research is needed in large populations with large exposure contrasts. Additional cross-sectional studies of low exposed populations may be less informative., (Copyright © 2020. Published by Elsevier Ltd.)

Substantial perfluoroalkyl acids (PFAAs) production still occurs in China, and the consumption of aquatic products is a critical exposure pathway of PFAAs in humans. In this study, specimens of 16 freshwater and 40 marine species were collected in the river-estuary-sea environment affected by a mega fluorochemical industry park in China in 2015, and the edible tissues of these organisms were analyzed for PFAA levels. Perfluorooctanoic acid (PFOA) was the dominating contaminant with an overall contribution of more than 90%, and concentrations as high as 2161 ng/g wet weight (measured in the freshwater winkle). All species with the greatest PFOA levels were benthic. The trophic magnification factor (TMF) of PFOA was 1.10 for freshwater species and 1.28 for marine species, indicating that PFOA was slightly magnifying. Analysis of carbon source indicated that freshwater species were more benthic feeding, while marine species were more pelagic feeding. Aquatic food consumption screening values of PFOA were modified according to estimated daily intake (EDI) values, which generated recommendations for limited meal categories and the do-not-eat category. Thus, this study provides recommendations for mitigating the health risks of PFAA-contaminated aquatic food, ranging from food selection to consumption frequency and proper food processing., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Persistent organic pollutants (POPs) are linked with insulin resistance and type-2 diabetes (T2D) in the general population. However, their associations with gestational diabetes (GDM) are inconsistent., Objective: We prospectively evaluated the associations of POPs measured in early pregnancy with GDM risk. We also assessed whether pre-pregnancy BMI (ppBMI) and family history of T2D modify this risk., Methods: In NICHD Fetal Growth Study, Singletons, we measured plasma concentration of 76 POPs, including 11 organochlorine pesticides (OCPs), 9 polybrominated diphenylethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 per-and polyfluoroalkyl substances (PFAS) among 2334 healthy non-obese women at 8-13 weeks of gestation. GDM was diagnosed by Carpenter and Coustan criteria. We constructed chemical networks using a weighted-correlation algorithm and examined the associations of individual chemical and chemical networks with GDM using multivariate Poisson regression with robust variance., Results: Higher concentrations of PCBs with six or more chlorine atoms were associated with increased risk of GDM in the overall cohort (risk ratios [RRs] range: 1.08-1.13 per 1-standard deviation [SD] increment) and among women with a family history of T2D (RRs range: 1.08-1.48 per 1-SD increment) or normal ppBMI (RRs range: 1.08-1.22 per 1-SD increment). Similar associations were observed for the chemical network comprised of PCBs with ≥6 chlorine atoms and the summary measure of total PCBs and non-dioxin like PCBs (138, 153, 170, 180). Furthermore, four PFAS congeners - perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluoroheptanoic acid (PFHpA), and perfluorododecanoic acid (PFDoDA) - showed significant positive associations with GDM among women with a family history of T2D (RRs range:1.22-3.18 per 1-SD increment), whereas BDE47 and BDE153 showed significant positive associations among women without a family history of T2D., Conclusions: Environmentally relevant levels of heavily chlorinated PCBs and some PFAS and PBDEs were positively associated with GDM with suggestive effect modifications by family history of T2D and body adiposity status., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Multiple agencies have developed health-based toxicity values for exposure to perfluorooctanoic acid (PFOA). Although PFOA exposure occurs in utero and through breastfeeding, current health-based toxicity values have not been derived using fetal or child dosimetry. Therefore, current values may underestimate the potential risks to fetuses and nursing infants., Objective: Using fetal and child dosimetry, we aimed to calculate PFOA maternal human equivalent doses (HEDs), corresponding to a developmental mouse study lowest observed adverse effect level (LOAEL, 1mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs., Methods: First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1mg PFOA/kg/day for gestational days 1-17. Four plasma PFOA concentration metrics were estimated in pups: i) average prenatal; ii) average postnatal; iii) average overall (prenatal and postnatal); and iv) maximum. Then, Monte Carlo simulations were performed using a pharmacokinetic model of pregnancy and lactation in humans to generate distributions of maternal HEDs that would result in fetal/child plasma levels equivalent to those estimated in pups using the mouse model. Median (HED 50 ) and 1st percentile (HED 01 ) of calculated HEDs were calculated., Results: Estimated PFOA maternal HED 50 s ranged from 3.0×10 -4 to 1.1×10 -3 mg/kg/day and HED 01 s ranged from 4.7×10 -5 to 2.1×10 -4 mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3×10 -3 mg/kg/day)., Conclusion: Our results suggest that fetal/child dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Prenatal perfluorooctanoate (PFOA) exposure has been associated with reduced birth weight but maternal glomerular filtration rate (GFR) may attenuate this association. Further, this association remains unclear for other perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). We estimated associations between prenatal PFAS exposure and birth outcomes, and the influence of GFR, in a Spanish birth cohort., Methods: We measured PFHxS, PFOS, PFOA, and PFNA in 1st-trimester maternal plasma (years: 2003-2008) in 1202 mother-child pairs. Continuous birth outcomes included standardized weight, length, head circumference, and gestational age. Binary outcomes included low birth weight (LBW), small-for-gestational-age, and preterm birth. We calculated maternal GFR from plasma-creatinine measurements in the 1st-trimester of pregnancy (n=765) using the Cockcroft-Gault formula. We used mixed-effects linear and logistic models with region of residence as random effect and adjustment for maternal age, parity, pre-pregnancy BMI, and fish intake during pregnancy., Results: Newborns in this study weighted on average 3263g and had a median gestational age of 39.8weeks. The most abundant PFAS were PFOS and PFOA (median: 6.05 and 2.35ng/mL, respectively). Overall, PFAS concentrations were not significantly associated to birth outcomes. PFOA, PFHxS, and PFNA showed weak, non-statistically significant associations with reduced birth weights ranging from 8.6g to 10.3g per doubling of exposure. Higher PFOS exposure was associated with an OR of 1.90 (95% CI: 0.98, 3.68) for LBW (similar in births-at-term) in boys. Maternal GFR did not confound the associations., Conclusions: In this study, PFAS showed little association with birth outcomes. Higher PFHxS, PFOA, and PFNA concentrations were non-significantly associated with reduced birth weight. The association between PFOS and LBW seemed to be sex-specific. Finally, maternal GFR measured early during pregnancy had little influence on the estimated associations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

On 25th May 2016, the U.S. EPA released reference doses (RfDs) for Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) of 20ng/kg/day, which were much more conservative than previous values. These RfDs rely on the choices of animal point of departure (PoD) and the toxicokinetics (TK) model. At this stage, considering that the human evidence is not strong enough for RfD determination, using animal data may be appropriate but with more uncertainties. In this article, the uncertainties concerning RfDs from the choices of PoD and TK models are addressed. Firstly, the candidate PoDs should include more critical endpoints (such as immunotoxicity), which may lead to lower RfDs. Secondly, the reliability of the adopted three-compartment TK model is compromised: the parameters are not non-biologically plausible; and this TK model was applied to simulate gestation and lactation exposures, while the two exposure scenarios were not actually included in the model structure., (Copyright © 2017. Published by Elsevier Ltd.)

As an emerging persistent organic pollutant (POP), perfluorooctanoate (PFOA) is one of the most abundant perfluorinated compounds (PFCs) in the environment. This review summarized the molecular mechanisms and signaling pathways of PFOA-induced toxicity in animals and humans as well as their implications for health risks in humans. Traditional PFOA-induced signal pathways such as peroxisome proliferating receptor alpha (PPARα), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and pregnane-X receptor (PXR) may not be important for PFOA-induced health effects on humans. Instead, pathways including p53/mitochondrial pathway, nuclear lipid hyperaccumulation, phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT), and tumor necrosis factor-α/nuclear factor κB (TNF-α/NF-κB) may play an important role for PFOA-induced health risks in humans. Both in vivo and in vitro studies are needed to better understand the PFOA-induced toxicity mechanisms as well as the associated health risk in humans., (Published by Elsevier Ltd.)

Introduction: Thyroid hormones (THs) are especially important for brain maturation and development during the fetal period and childhood. Several epidemiological studies have assessed the possible association between exposure to perfluoroalkyl substances (PFAS) and thyroid outcomes during the early stages of life. We aimed to review this evidence., Methods: We conducted a systematic review in compliance with the PRISMA Statement (search conducted in PubMed and Embase, as well as in the citations of the selected articles). We chose studies if they dealt with thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxin (T4), or thyroid dysfunctions, and perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) or perfluorononanoic acid (PFNA) measured in the blood of pregnant women and/or children up to 19years old., Results: We included in this review three cross-sectional, one case-control, and six cohort studies (publication: 2011-2015), focusing on prenatal life (n=7), childhood (n=2) or both periods (n=1). We observed a high degree of heterogeneity across studies in terms of sampling time (different gestational weeks, at birth, or childhood), outcomes, adjustment for potential confounders, and statistical approach. We found some evidence of a positive association between PFHxS and PFOS exposure and TSH levels measured in maternal blood, and PFNA and TSH levels measured in the blood of boys aged ≥11years., Conclusion: Although there is a small number of studies with comparable data, we found some consistency of a positive association between maternal or teenage male exposure to some PFAS and TSH levels based on the current literature. However, further studies are required to confirm these possible relationships., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluoroalkyl substances (PFASs) are chemicals with potential neurotoxic effects although the current evidence is still limited. This study investigated the association between perinatal exposure to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and neuropsychological development assessed at 6, 12 and 24 months. We measured PFOS and PFOA in breast milk samples collected one month after delivery by mothers of children participating in the HUMIS study (Norway). Cognitive and psychomotor development was measured at 6 and at 24 months using the Ages and Stages Questionnaire (ASQ-II). Behavioral development was assessed using the infant-toddler symptom checklist (ITSC) at 12 and at 24 months. Weighted logistic regression and weighted negative binomial regression models were applied to analyze the associations between PFASs and ASQ-II and ITSC, respectively. The median concentration of PFOS was 110 ng/L, while the median for PFOA was 40 ng/L. We did not detect an increased risk of having an abnormal score in ASQ-II at 6 months or 24 months. Moreover, no consistent increase in behavioral problems assessed at 12 and 24 months by ITSC questionnaire was detected. We observed no association between perinatal PFOS and PFOA exposure and early neuropsychological development. Further longitudinal studies are needed to confirm the effects of these compounds on neuropsychological development in older children., (Copyright © 2015. Published by Elsevier Ltd.)

Perfluorooctanoic acid (PFOA, 'C8') and perfluoroctane sulphonate (PFOS) are environmentally stable compounds with industrial and consumer uses and long half-lives in humans. Concern has been raised over chronic exposure effects to human health, especially in relation to cholesterol metabolism. Here, we explore the association between exposure to PFOA and PFOS and the in vivo expression of genes involved in cholesterol metabolism. We studied 290 individuals exposed to background levels of PFOS and elevated concentrations of PFOA through drinking water. Using adjusted linear regression models, we found inverse associations between serum PFOA levels and the whole blood expression level of genes involved in cholesterol transport (NR1H2, NPC1 and ABCG1; p=0.002, 0.026 and 0.014 respectively). A positive association was seen between PFOS and a transcript involved in cholesterol mobilisation (NCEH1; p=0.018), and a negative relationship with a transcript involved in cholesterol transport (NR1H3; p=0.044). When sexes were analysed separately, reductions in the levels of mRNAs involved in cholesterol transport were seen with PFOA in men (NPC1, ABCG1, and PPARA; p=0.025, 0.024 and 0.012 respectively) and in women (NR1H2 expression; p=0.019), whereas an increase in the levels of a cholesterol mobilisation transcript (NCEH1; p=0.036) was noted in women alone. PFOS was positively associated with expression of genes involved in both cholesterol mobilisation and transport in women (NCEH1 and PPARA; p=0.003 and 0.039 respectively), but no effects were evident in men. This is the first report of associations between the in vivo expression of genes involved in cholesterol metabolism and exposure to PFOA or PFOS, suggested that exposure to these compounds may promote a hypercholesterolaemic environment, with wider implications for human disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)